Serotonin (5HT) plays a major role in breathing and the control of upper airway function. The proposed research will test the hypothesis that, with increasing age, there is a gender- specific decrease in serotonergic modulation of respiratory motoneurons. Because of gender-related differences, aging males may be uniquely susceptible to breathing disorders such as obstructive sleep apnea. Our preliminary data indicate that 5HT immunoreactivity in the hypoglossal nucleus decreases with age in male rats, but increases with age in female rats. Furthermore, long term facilitation, a 5HT-dependent increase in respiratory motor output following intermittent hypoxia, decreases to older male rats, but increases to older female rats. This is the first description of age-associated change in serotonergic modulation of respiratory control, and the first description of sexual dimorphism in age-related changes in any aspect of the serotonergic nervous system. The proposed research will test the hypothesis that gonadal hormones have a neuroprotective role in the maintenance of serotonergic modulation of respiratory motoneurons in female rats with increasing age, and can potentially reverse or delay the age-associated changes that occur in male rats. Five specific aims are proposed, each corresponding to a testable hypothesis. First, we will use neurochemical and anatomical assays to detect age- and gender- related changes in key elements of the serotonergic neuromodulatory system (5HT, 5HT receptors, and the serotonin reuptake transport protein) in hypoglossal and phrenic motor nuclei. Secondly, we propose to determine if there are functional consequences of aging and gender on respiratory responses to hypoxia in awake rats. Thirdly, we will test the hypothesis that serotonin-dependent components of the hypoxic ventilatory response are decreased selectively with aging in male rats. Finally, we propose to investigate the influence of neutering and hormone replacement therapy (estrogen, progesterone, testosterone) on our anatomical and physiological indices of serotonergic modulation of respiration in male and female rats. To our knowledge, this is the first proposal to study age and gender effects on any form of plasticity in respiratory control. An understanding of these mechanisms may lead to therapeutic strategies for intervention in age-related breathing disorders that affect both men and women such as obstructive sleep apnea.